For many years, developmental and physiological differences have been known to exist between anatomic segments of the colorectum. Because of different outcomes, prognoses, and clinical responses to chemotherapy, the distinction between right colon cancer (RCC) and left colon cancer (LCC) has gained attention. Furthermore, variations in the molecular features and gut microbiota between right and LCCs have recently been a hot research topic. CpG island methylator phenotype-high, microsatellite instability-high colorectal cancers are more likely to occur on the right side whereas tumors with chromosomal instability have been detected in approximately 75% of LCC patients and 30% of RCC patients. The mutation rates of oncogenes and tumor suppressor genes also differ between RCC and LCC patients. Biofilm is more abundant in RCC patients than LLC patients, as are Prevotella, Selenomonas, and Peptostreptococcus. Conversely, Fusobacterium, Escherichia/Shigella, and Leptotrichia are more abundant in LCC patients compared to RCC patients. Distinctive characteristics are apparent in terms of molecular features and gut microbiota between right and LCC. However, how or to what extent these differences influence diverging oncologic outcomes remains unclear. Further clinical and translational studies are needed to elucidate the causative relationship between primary tumor location and prognosis.